January 2013

www.medicaltribune.com

New advisory recommends fewer GERD endoscopies

FORUM TB in children: We need to do more

SINGAPORE FOCUS Worlds first dissolvable drug-eluting stent

CONFERENCE Rapid TB test performs well

IN PRACTICE Managing COPD in primary care

January 2013

New advisory recommends fewer GERD endoscopies

Radha Chitale

ew recommendations for patients with gastroesophageal reflux disease (GERD) advise physicians to avoid unnecessary endoscopies in patients for whom there is little benefit. Upper endoscopy is a routine procedure for GERD diagnosis and management, particularly when monitoring for abnormal or cancerous esophageal tissue, but overuse results in higher healthcare costs and adverse side effects without improved patient outcomes. Limited data suggest that clinicians who care for patients with GERD symptoms often do not follow suggested practice, according to the Clinical Guidelines Committee of the American College of Physicians. The Committee noted that 10-40 percent of upper endoscopies are not generally indicated but are performed for patients with GERD symptoms without additional dysplasia, are performed too often, or are performed before alarm symptoms occur. The best practice recommendations indicate upper endoscopy for patients with heartburn and alarm symptoms including dysphagia, bleeding, anemia, weight loss or recurrent vomiting. [Ann Intern Med 2012;157:808-816] Upper endoscopy is also indicated for patients who persist with GERD symptoms even after a 4-8 week course of acid-reducing proton pump inhibitor therapy, who persist with severe esophagitis, or who have a history of a narrowed esophagus. Persistent GERD can lead to Barretts

esophagus, in which the esophageal lining erodes and is replaced by stomach lining tissue, and both are associated with increased risk of esophageal adenocarcinoma. However, 80 percent of all cancers occur in men, so screening for cancer or Barretts esophagus via endoscopy is recommended for men over 50 with GERD. If endoscopic screening of patients with GERD symptoms is to be pursued, men older than 50 years will provide the highest yield of both Barretts esophagus and early adenocarcinoma, the researchers said. But both men and women with a history of Barretts esophagus may be screened every 3-5 years via endoscopy for dysplasia or cancerous cells. Up to 85 percent of GERD patients have non-erosive reflux disease. And while upper endoscopy is a relatively low-risk procedure, it can cause respiratory failure, hypotension, reactions to anesthetics, and in extreme cases, perforation and cardiovascular events. The committee based their recommendations on a literature review and comparison of clinical guidelines from other professional organizations. Because of its high prevalence in the general population, care of patients with GERD is largely within the domain of primary care providers, they said. Upper endoscopy is not an appropriate first step in most patients with GERD symptoms and is indicated only when empirical PPI therapy for 4-8 weeks is unsuccessful.

January 2013

Blood protein resistin reduces statin effect in obese

Rajesh Kumar

anadian researchers have identified a protein called resistin, secreted by fat tissue, as the cause of elevated low-density lipoprotein (LDL) in obese people. Their research, presented at the Canadian Cardiovascular Congress recently held in Toronto, Ontario, Canada, has shown that resistin increases the production of LDL in human liver cells and also degrades LDL receptors in the liver. As a result, the liver is less able to clear LDL from the body. Resistin also reduces the efficacy of statins, so much so that a staggering 40 percent of patients taking statins cannot lower their blood LDL, said senior author Dr. Shirya Rashid, assistant professor in the department of medicine at McMaster University in Hamilton, Ontario, Canada. The bigger implication of our results is that high blood resistin levels may be the cause of the inability of statins to lower patients LDL cholesterol, said Rashid, adding that the discovery could lead to revolutionary new therapeutic drugs, especially those that target and inhibit resistin and

High resistin levels may attenuate the LDL cholesterol-lowering effects of statins.

thereby increase the effectiveness of statins. Dr. Goh Ping Ping, medical director of the Singapore Heart Foundation, termed the research findings as progressive medical evidence saying they reinforce the importance of treating cholesterol levels to goal in order to reduce cardiovascular risk. [But] this can be challenging in some high-risk patients whose target cholesterol level has to be very low. Hence, we welcome new developments in medical therapy to help patients reach their target levels safely, said Goh. As physicians, we need to also continuously motivate patients to exercise and adhere to a heart healthy diet.

January 2013

Forum

TB in children: We need to do more

Excerpted from a presentation by Dr. Anneke Hesseling, director of the Paediatric TB Research Program at the Desmond Tutu TB Centre at Stellenbosch University in Cape Town, South Africa, during the 43rd Union World Conference on Lung Health, held recently in Kuala Lumpur, Malaysia.

t is estimated that 500,000 children become ill with tuberculosis (TB) and that 70,000 affected children die annually, but these figures still do not reflect the true global burden of TB. Childhood TB is an indication of recent transmission, as children tend to acquire the infection in the first year of life, and as such is an indication of household dynamics and epidemiology, especially the emergence of drug resistance in the community. Therefore, TB in children is a litmus test indicating how well we are doing with TB control, and clearly we are failing. Historical approach The traditional approach to childhood TB has been the assumption that proper identification and treatment of infectious adult cases will prevent childhood TB. But children are not the same as small adults. They have a developing immune system, which makes them especially susceptible to severe forms of TB such as TB meningitis. And childhood TB is typically a lowpriority disease for national tuberculosis programs (NTP) because it is difficult to diagnose with a smear test, it is not usually infectious, there are limited resources to tackle TB treatment, and there are a lack of recording and reporting approaches. Only about two-thirds of cases are actually notified to NTPs. A cross-sectional study from Indonesia

A childs developing immune system makes them susceptible to forms of TB.

showed that only 1.6 percent of 4,821 cases of child TB were registered with the NTP there. [BMC Public Health 2011;11:784] Despite available therapies, children have been systematically neglected in a way that has led to preventable morbidity and mortality. Progress The good news is that for the first time, childhood TB is on the public health agenda, with strong leadership from the WHO and other dedicated groups. Children have been included in guidelines for NTPs and these have been updated in the last several years including reporting practices, dosage revision for young children to avoid hepatotoxicity, and guidance on managing TB/HIV co-infections.

January 2013

Forum
where we are going and be honest about assessing achievements and failures. Research A decade ago, we did not have any new anti-TB drugs. In children, there was limited evidence for rational TB drug use. There were few rapid diagnostic tests, especially for smear-negative TB and drug-resistant TB, and there were no TB vaccines in human trials. So we really have come a long way, but there are still considerable gaps in TB research. Drug formulations tend not to be childfriendly they are unpalatable and difficult to give in accurate doses since tablets must be broken. However, research has shown that individualized tailored treatment can dramatically improve outcomes, even among those with drug-resistant TB more than 80 percent of children with multi-drug resistant TB can achieve favorable outcomes, even in the context of HIV positivity. [Clin Infect Dis 2012 Jan 15;54:157-166] However, these regimens are not easily handled. Requiring injections, they work better in older children and some therapies can cause significant hearing loss. More research is required to develop safer multi-drug resistant TB therapy regimes that are shorter and easier to use. No rigorous evidence-based management for drug-resistant TB preventive therapy is available for adults, much less for children. Trials to evaluate new therapies and regimes should include children and adults. Diagnostics The challenges in TB diagnosis, which tends to be underfunded, have been a big burden for recognizing TB in the public health framework.

However, despite good policies, implementation can be an issue, especially given looming funding deficits, which affect countries with limited resources in particular. Some methods to combat these barriers would be to integrate families in childhood TB care, including pregnant women and those with HIV infection, in order to consolidate services. Every clinic visit should be an opportunity to ask about a household TB contact. Empowering healthcare workers at all levels to get involved in TB care can yield better disease reporting statistics. A program in four hospitals in Jakarta, Indonesia, showed that TB diagnosis rates were similar between nurses, general practitioners and pediatricians when they received specific training. Pragmatic, simple models of care should be implemented where possible. In one study, directly observed onceweekly treatments for 12 weeks with a combination of rifapentine and isoniazid was as effective in adults, if not more, as daily isoniazid-only therapy for 9 months, which could be a better model for treating children. [N Engl J Med 2011;365:2155-2166]

Despite available systematically neglected

therapies, children have been

Partnerships and collaborations with industry could also help improve drug availability and make available new pediatric first-line fixed dose combinations. But for this market research on barriers to treatment, current practice for uptake and accurate estimates on childhood TB to quantify the market are required. For the global TB community, setting short- to medium- and long-term goals, and being accountable for them, will help us see

January 2013

Forum
time to diagnosis and are better at recognizing TB and drug-resistant TB, even in children. Conclusion Childhood TB is coming of age and we are at a unique juncture of increased public health awareness, advocacy and funding for clinical and implementation research. Last year, World TB Day focused on children, an indication that the field is moving forward. More progress will require working together in a sustained manner, monitoring progress in order to reach the final goal, which is a generation of children free of TB.

It does not help that the reference standard liquid culture is imperfect in children and misses a large portion of children with clinical disease that isnt bacteriologically proven. Children are usually an afterthought when new diagnostics get implemented and evaluated. However, childhood TB naturally presents with fewer bacterial units. Sometimes the TB community has been its own worst enemy by making the situation more complicated than it is. In fact, children should be managed on a daily basis to help demystify diagnosis and make it more accessible. New technologies that analyze DNA slash

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January 2013

Singapore Focus

New initiatives by Eastern Health Alliance

A team of nurses, therapists and doctors simulating the resuscitation of a SARS patient with cardiac arrest at SCI, as President Tony Tan and others look on.

ingapore President Dr. Tony Tan recently launched the Centre for Innovation (CFI) and Changi Simulation Institute (CSI) two new initiatives by the Eastern Health Alliance to meet healthcare challenges arising from an ageing population and growth in chronic diseases. The CFI will provide a platform and resources for generating ideas, prototyping them and creating partnerships for healthcare innovations, while CSI will provide relevant medical simulation training for teams of doctors, nurses and allied health professionals. Located alongside Changi General Hospitals training center, the facilities are open to the members of the alliance and other healthcare partners and will drive healthcare innovation and clinical competencies, respectively. The alliance will also join A*STARs ongoing collaboration with the Center for the Integration of Medicine and Innovative Technology (CIMIT) in Boston, Massachusetts, US. This will allow it to benefit from CIMITs expertise in developing medical technologies and solutions, as well as from A*STARs science and engineering research capabilities.

January 2013

Singapore Focus

GSK expands manufacturing capabilities

laxoSmithKline (GSK) officials detailed plans to continue expanding in Asian markets, maintaining their operational headquarters in Singapore, during a recent celebration of 40 years of local pharmaceutical manufacturing. In the last 12 months, we had positive data on 10 new drugs... and were going to file for global approval for six new major medicines before the end of the year, said GSK CEO Sir Andrew Witty. Over the next 3 years we should launch about 15 new medications. Among the drugs in the pipeline will be therapies for HIV, malaria and muscular dystrophy. Witty said Singapore will play a key role in the manufacture of these new drugs, should they be approved for use. Singapores Prime Minister Lee Hsien Loong said GSKs strategy was an important indicator of the value of manufacturing for a large region. Manufacturing will remain important for [Singapores] economy even as it changes, he said.

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January 2013

Singapore Focus

HPB takes senior citizens back to school

o improve health literacy and empower senior citizens to make healthier choices, Singapores Health Promotion Board (HPB) has developed and piloted a new program in Choa Chu Kang community. The Back to School program incorporates classroom workshops, hands-on and experiential educational activities to help residents and their caregivers understand, for example, the importance of home safety, good oral health and flu vaccination. It also provides senior citizens access to dental and functional screening services and vaccination for influenza. The program, jointly implemented by HPB and Choa Chu Kang Grassroots Organization and the South View Primary School, will be expanded to more constituencies next year. Minister for Health and MP for Choa Chu Kang GRC, Gan Kim Yong, said the project is innovative and meaningful and will greatly benefit Choa Chua Kang residents. HPBs chief executive officer, Ang Hak Seng, said there is a low level of flu vaccine uptake among the elderly, with only one in 10 residents aged 50 to 69 vaccinated in 2011. The program not only allows them to be healthy, but to receive flu vaccine and get routine dental check under one roof.

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January 2013

Singapore Focus

Worlds first dissolvable drug-eluting stent

Rajesh Kumar

he worlds first drug-eluting bioresorbable stent promises to revolutionize the care for patients with coronary artery disease (CAD). Absorb (Abbott Vascular) is made from a naturally dissolvable material called polylactide that is commonly used in dissolving sutures and is coated with the anti-proliferative drug everolimus. It works by restoring blood flow in the blocked coronary artery similar to a metallic drug-eluting stent but then dissolves into water and carbon dioxide within a few months, leaving behind a treated vessel that may resume its natural elasticity and pulsating movement. The device is being referred to as scaffold rather than stent to indicate its temporary nature and is creating quite a stir amongst interventional cardiologists. There have been three significant milestones in the treatment of CAD in the last few decades angioplasty, bare metal stents and drug-eluting stents. The fourth and latest revolution has been initiated with the introduction of Absorbit has the potential to transform the way we treat patients, said Dr. Pieter Cornelis Smits, director of interventional cardiology at Maasstad Ziekenhuis in Rotterdam, the Netherlands. With Absorb, the vessel may return to a more natural state over time, which could provide patients with important clinical benefits over the long-term. A stent is usually not required after about 6 months of treatment by when the artery gets unblocked and can stay open on its own.

Absorb, a drug-eluting stent made from polylactide, a naturally dissolvable material.

Some patients may require repeat stenting due to reblockage on either the same or on different sites. As a result, their arterial walls end up becoming rigid in many places due to multiple metal stents left behind, explained Smits.

It has the potential to transform the way we treat patients

Absorb leaves behind only two pairs of tiny metallic markers which help guide its placement and remain in the artery to enable physician to subsequently see where the device was placed. As a result, the vessel can expand and contract as needed to increase the flow of blood to the heart in response to activities such as exercise. The need for long-term treatment with anti-clotting medications may also be reduced and any subsequent interventions would be unobstructed, Smits added. Initial data from multiple ongoing studies in more than 20 countries around the world, including Singapore, indicate that Absorb

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January 2013

Singapore Focus
Middle East, parts of Asia Pacific including Hong Kong, Malaysia and New Zealand, and parts of Latin America. It is not yet registered in Singapore and is currently available through special access route, pending regulatory approval by Health Sciences Authority.

performs similar to a best-in-class drug-eluting stent across traditional measures such as major adverse cardiovascular events and target lesion revascularization, according to Abbott Vascular. Absorb is now available in Europe, the

NUS researchers knock down chikungunya

Elvira Manzano

esearchers from the National University of Singapores (NUS) Yong Loo Lin School of Medicine have identified a new gene silencing approach that can kill the chikungunya virus quickly, making prophylactic therapy possible for patients with this condition. By employing small hairpin RNA (shRNA) technology directed against two specific chikungunya virus, E1 and nsP1genes, Ms. Shirley Lam, a postgraduate student from NUS and her team, was able to show that the strategy knocked down the virus and suppressed replication in infected cells within 3 days. The approach, tested in both human cells and mice models, was able to protect the cells for up to 15 days, said Lam who received the Singapore Young Scientist Award at the recent Singapore Health and Biomedical Congress for her work. Our findings reinforce the potential usefulness of shRNA technology in clinical settings of chikungunya virus infection. Chikungunya shares some clinical symptoms with dengue. You really need a good diagnostic lab component to come into a play, said principal investigator Assistant

Principal investigator Dr. Chu Jang Hann (center), lab executive Chen Huixin (left) and lead researcher Shirley Lam (right) examine an X-ray film of chikungunya virus protein expression profile.

Professor Justin Hang-Hann Chu, of the Department of Microbiology, NUS Yong Loo Lin School of Medicine. A PCR [polymerase chain reaction] is sensitive enough to tell the difference. Patients with chikungunya present with a sudden onset of fever, chills, headache, nausea and vomiting, joint pain with or without swelling, rash and low back pain. Currently, there is no vaccine or specific treatment for chikungunya infection. Treatment is primarily focused at relieving symptoms which can drag on for months, or even years. We have shown that shRNA antiviral technology was effective in inhibiting the

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January 2013

Singapore Focus
pore experienced between 2008 and 2010 where we had close to 1,000 chikungunya cases. The study was funded by the Agency for Science, Technology and Researchs (A*STAR) Biomedical Research Council. Chus team is now working to translate their study results into clinical applications.

virus. Its even highly specific for chikungunya, Chu said. Were looking at it as a possible prophylactic treatment to reduce cases of infection. Unlike vaccines which provide long-term protection, the approach only gives shortterm protection. However, it can be useful during an outbreak, similar to what Singa-

Nine-year-old CKD patient plays scientist

Radha Chitale

espite having chronic kidney disease (CKD) for the majority of her life, 9-year-old Meenakshi Sundaram Losheni has not felt deterred from laboratories. On the contrary, science is her favorite subject and she recently donned a lab coat to join scientists at Singapores Institute of Bioengineering and Nanotechnology (IBN) to participate in their research for a day. Our researchers are developing nextgeneration technologies for organ replacement and regenerative medicine, and volunteer opportunities such as this inspire them by putting a face to the biomedical problems that they are working on, said Professor Jackie Y. Ying, IBN Executive Director. People with CKD progressively and irreversibly lose kidney function. As a result, waste builds up in the kidneys, leading to fatigue, low appetite, high blood pressure and nerve and blood vessel damage. Losheni receives hours of dialysis each night, in addition to medication every day. In adults, diabetes and high blood pressure are the primary causes of CKD but chil-

dren may get the disease as a result of a number of afflictions such as obstructive urology and kidney cysts. Children are commonly affected between ages 2-5.

Volunteer opportunities such as this inspire

In patients with CKD, progression to end stage renal disease (ESRD) is inevitable and kidney transplants are required. About 70 percent of children with CKD will develop ESRD by age 20; the 10-year survival rate is 80 percent. Death occurs most often due to cardiovascular disease and infection. IBN partnered with the Make-A-Wish Foundation Singapore to bring Losheni to their facility in Biopolis. She was able to examine stem cells from liver, bone and kidney that might be used in tissue engineering and present her findings to the lab group. Mr. Paul Heng, board chair of the Makea-Wish Foundation Singapore, said he hoped that the experience, aside from fulfilling Loshenis intellectual curiosity, would prepare her for her own kidney transplant.

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January 2013

Singapore Focus

Bone loss may be an issue after bariatric surgery

Rajesh Kumar

keletal examination before and after bariatric surgery and treatment for potential bone loss should form part of patient care, experts cautioned following review of several research findings suggesting bariatric surgery may cause bone loss particularly in young people. In most developed countries, Roux-en-Y gastric bypass surgery is the most invasive and commonly used method involving removal of much of the stomach and bypassing of part of the small bowel, while gastric sleeve and gastric band are the less radical methods of obesity surgery. [Obesity Reviews 2012; DOI: 10.1111/j.1467-789X.2012.01050.x] Even though we dont yet understand all the mechanisms, we can see that the more radical the procedure, the greater the bone loss long-term, said researcher endocrinologist Dr. Malgorzata Brzozowska of the Garvan Institute of Medical Research in Sydney, Australia. In many situations significant weight loss is associated with bone loss, with or without surgery. The more invasive types of surgery appear to heighten bone turnover and the associated bone loss, she said. This is thought to be caused not only by rapid weight loss and absorption of fewer vital nutrients like vitamin D and calcium, but possibly also by changes in hormones released by fat and the gut, and their impact on the central nervous system. Physicians should be aware of surgery-

Weight loss is often linked to bone loss, with or without surgery

induced changes in hormones that can affect the central regulation of appetite and bone strength. These include the fat-derived hormones leptin and adiponectin; gut-derived hormones such as peptide YY (PYY), glucagon-like peptide 1 (GLP-1) and ghrelin; and the hypothalamic regulator of energy balance, neuropeptide Y (NPY), the review pointed out. As the number of bariatric operations increases, Brzozowska said it was imperative to recognize mechanisms responsible for bariatric surgery-induced bone loss, with careful monitoring of bone health including longterm fracture incidence in patients undergoing these procedures. Associate Professor Jackie Center, also of the Garvan Institute, said the widely held assumption that obese people were protected against bone fragility and fracture was true only up to a point.

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January 2013

Singapore Focus
tions are associated with a low probability of clinically significant bone loss, but patients with these operations already have their bone mass monitored and take calcium and vitamin D supplements. With the purely restrictive operations such as lap-band and lap sleeve gastrectomy, the risk of bone loss is almost negligible and patients need not routinely take calcium and vitamin D supplements, said Baladas. Studies like these are very important because the number of bariatric operations for morbid obesity is increasing in Asia. In Singapore alone, more than a thousand patients have undergone bariatric surgery for morbid obesity, he concluded.

Therefore, on all those undergoing invasive bariatric surgery, bone mineral densitometry scans can be done and adequate calcium and vitamin D intake advised. For those patients at particular risk, additional monitoring may be advised and protective drugs considered. Dr. H.G. Baladas of the Raffles Surgery Centre at Raffles Hospital, Singapore said surgeons were well aware of the risks and thats why bariatric surgery is rarely offered to younger patients who have not yet reached optimum bone growth. Pure bypass operations such as jejunoileal bypass result in the highest bone loss, but are no longer being performed, he said, adding that combined bypass and restriction opera-

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January 2013

Singapore Focus

Singapore continues to pour funds into biomedical research

Radha Chitale

rants worth over S$100 million have been awarded to eight biomedical research programs in Singapore that target important diseases in the Asia-Pacific region. The programs, some new and some ongoing, should help Singapores biomedical sciences sector evolve into a symbiotic web of laboratory research, clinical care and research and industry partnership that will support the countrys bid to turn biomedical sciences into a key economic contributor. One of Singapores key differentiating and competitive value propositions is our ability to integrate our research efforts along the innovation value chain as well as across multiple research organizations, said Mr. Lim Chuan Poh, chairman of the Agency for Science, Technology and Research (A*STAR) and co-chair of the Biomedical Sciences Executive Committee. We have to make sure that Singapore continually occupies an advantage in this [competitive environment] to make sure to constantly create high-value jobs in Singapore. Supported by the National Medical Research Council of the Ministry of Health, four Translational and Clinical Research (TCR) Flagship grants totalling S$68 million were awarded to research programs in eye disease, gastric cancer, heart disease and non-small cell lung cancer. Each of these research areas have strong, established scientific and clinical capabilities

Over S$100 million in grants have been awarded to eight biomedical research programs in Singapore.

in Singapore because they are diseases with high-burden and unique presentation among Asian populations. The research program on corneal disease and glaucoma, led by Professor Donald Tan of the Singapore National Eye Centre, and the Singapore Gastric Cancer Consortium, led by Assistant Professor Khay Guan Yeoh at the National University Singapore, were each awarded S$25 million over 5 years. Two more grants, worth S$9 million over 5 years, were given to researchers at the National Heart Centre Singapore and the National Cancer Centre Singapore to study heart disease and non-small-cell lung cancer. Another S$58.4 million from Singapores Strategic Positioning Fund were awarded to projects within A*STAR. The standout project is the POLARIS (Personalized OMIC Lattice for Advanced Research and Improving Stratification) initiative, which will receive S$20 million over the next 3 years to improve stratified, or personalized, medicine by organizing existing local

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January 2013

Singapore Focus
into common ailments, said the Genetic Orphan Diseases Programme program lead Dr. Bruno Reversade, senior principal investigator at A*STARs Institute of Molecular Biology. Two other projects to analyze circulating cancer cells and to develop predictive biomarkers will also each receive S$12.3 million and S$13.4 million, respectively. Key performance indicators, including product development and health outcomes, will be monitored for these projects. This initiative is adding significantly to Singapores GDP [gross domestic product], said Sir Richard Sykes, chair of the Biomedical Sciences International Advisory Council. There has to be some measure of output.

biomarker research and clinical assays into a pipeline to speed diagnostic and treatment capabilities as well as identify new biomarkers for potential therapies. Its very important that Singapore be seen at the forefront of these developments in [stratified medicine], said Professor Stephen Smith, vice president (Research) of Nanyang Technological University. Another project seeks to identify larger trends in disease development through close examination of rare disease that are often single cases, and will receive S$12.7 million over three years. By understanding the rare, you understand the common because you have inroads

POLARIS initiative hones in on personalized medicine

Radha Chitale

S$20 million initiative by Singaporean research institutes and hospitals to link biomarker technology and clinical practice could help get specialized therapies to patients who need them. The POLARIS initiative will capitalize on existing genomic and metabolomic research in Singapore, particularly in diseases which have a large burden or a different presentation in Asian populations, based on the principles of stratified, or personalized, medicine. We want to transform disease management by moving away from a one-size-fitsall type of approach to targeting specific

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January 2013

Singapore Focus
Unresponsive patients who consent to participate in POLARIS would be evaluated once for biomarkers that match existing experimental therapies in ongoing clinical trials, which reduces the time it takes for them to receive treatment. Patients who remain unresponsive or who relapse may be evaluated further by whole genome sequencing and other types of biomarker analysis for novel diagnostic or therapeutic targets, to be tested in clinical trials. Pharmaceutical industry involvement to design clinical trials and develop new products will be a key facet of POLARIS. Its a more orchestrated system to enhance discoveries and findings based upon patients so that you are capturing the maximum amount of information from each patient with the minimum cost and the most efficiency, Tan said. Four institutes from A*STAR and clinicians from Singapore General Hospital, the National Cancer Centre Singapore, Singapore National Eye Centre and the National University Health System have partnered to be part of POLARIS. At present, POLARIS will focus on lung and gastric cancers and eye diseases, both because of the heavy local disease burden and because of the number of identified biomarkers. However, the initiative is scalable to other diseases and research groups. POLARIS is funded by a 3-year S$20 million grant from A*STARs Biomedical Research Council and represents the integration phase of Singapores initiative to grow the biomedical sciences sector.
*Personalized OMIC Lattice for Advanced Research and Improving Stratification

therapies to specific patient groups, said program lead Dr. Patrick Tan, of the Genome Institute of Singapore at the Agency for Science, Technology and Research (A*STAR). The challenge now lies in how to realize the clinical value of those initial [biomarker] discoveries. In order for that to happen, the technologies that we use to give rise to those discoveries must then be taken from the research center back into the clinics where these findings can be implemented in the form of certified clinical tests. Currently, there is no accredited facility to analyze biomarker assays in Singapore and patient samples must be sent overseas. Tan said they hope to set up a local facility, certified by the College of American Pathologists, to carry out standardized, robust testing on routine clinical samples that clinicians can feel comfortable using to allocate treatment. At the end of the day, we want the clinician to take the information and act on it, he said. The immediate impact on patients would be validated biomarker assays that quickly identify subgroups of patients who will respond to available therapies. However, a portion of patients do not respond to existing therapies. The current model for enrolling such patients in clinical trials to receive experimental therapies is time consuming and costly because assessing their eligibility is decentralized and requires multiple biomarker assays. For example a cancer patient at the National Cancer Centre Singapore must be evaluated several times to see if they are eligible for one of 4050 ongoing clinical trials. During this time, disease can progress, Tan said.

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January 2013

Conference Coverage

43rd Union World Conference on Lung Health, 13-17 November, Kuala Lumpur, Malaysia Radha Chitale reports

New TB therapies offer hope

wo promising new agents under development for treating multiple drugresistant tuberculosis (MDR-TB) cant be deployed fast enough, experts say. The US Food and Drug Administration (FDA) Anti-Infective Drugs Advisory Committee has approved a request for accelerated approval of drug-maker Janssens investigational agent bedaquiline for MDR-TB. Interim results of a randomized controlled phase II trial showed that the addition of bedaquiline to a five-drug background regimen (standard second-line drugs) for 24 weeks improved the rate of sputum culture conversion (shift from positive to negative Mycobacterium tuberculosis growth) in MDR-TB patients in a shorter time compared with the background regimen plus placebo (79 percent vs 58 percent, respectively). The effects of bedaquiline were durable out to a follow-up assessment at 72 weeks. Meanwhile, Otsuka Pharmaceuticals Group has filed for approval of another new TB agent delamanid with the European Medicines Agency (EMA). Delamanid has demonstrated increased sputum culture conversion at 2 months among patients with MDR-TB compared with placebo (45.4 percent vs 29.6 percent, respectively), plus background therapy for both groups, in a randomized controlled trial. [N Engl J Med 2012;366:2151-2160] Despite the possibility of approval of these new agents in the US and Europe, some are frustrated by the prospect of the lengthy up-

take process required to get new therapies to where they are really needed. Getting [drugs] approved in the US where we only have 130 cases of MDR-TB a year is really not going to be the place where these drugs are going to make the biggest difference, said Mr. Mark Harrington, executive director of the HIV/AIDS policy think tank Treatment Action Group. Countries that have weak regulatory systems are going to need a lot of political will and community demand to drive acceptance... On the ground youre going to need regulators, implementers and activists to work together to speed up not only the demand for the approved drugs but protocol review for experiments. Where normal treatment for drug-resistant TB requires a barrage of drugs for up to 2 years or more, novel drug regimens could shorten treatment courses and improve outcomes. But the time required for approval and implementation of a novel regimen against MDR-TB, one that would likely include bedaquiline and delamanid together, may prompt rapid implementation without regulatory goahead. I think the issue is what to do until we have better definitive evidence of a shorter regimen, said Dr. Mary Edginton of the University of the Witwatersrand School of Public Health in Johannesburg, South Africa. There doesnt seem to me to be any reason not to use the short course regimens, under

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January 2013

Conference Coverage
formulate some early or preliminary recommendations are gone. Of about 9 million cases of TB globally, about 630,000 are resistant to treatment, and 440,000 people with MDR-TB die each year according to the WHO Global Tuberculosis Report 2012.

research conditions, with informed consent of patients, and monitored and reported. Were going to need to pick up the pace, said Dr. Kenneth Castro, director of the Division of TB Elimination at the US Centers for Disease Control and Prevention. The times of waiting for the best possible evidence to

Intense antibiotic therapy may benefit TB meningitis patients

n intensified antibiotic treatment regimen could improve outcomes in patients with tubercular (TB) meningitis, according to an Indonesian study. We feel that our results challenge the current treatment model, said lead researcher Dr. Rovina Ruslami, of Padjadjaran University in Bandung, West Java, Indonesia. No optimal regimen for TB meningitis exists. However, as the pathophysiology of TB meningitis differs from pulmonary tuberculosis, Ruslami and colleagues have suggested that a higher drug dose may garner better treatment outcomes. In their open-label, phase II trial, 60 patients were randomized to receive a standard dose (450 mg orally) or high dose (600 mg intravenously) of rifampicin, after which they were divided again into groups to receive none, 400 mg, or 800 mg of oral moxifloxacin for 2 weeks, after which patients continued with standard tuberculosis treatment. Most patients were young (median age 28 years) and with advanced disease. Throughout the trial, patients received isoniazid and pyrazinamide, which penetrate well into the cerebrospinal fluid (CSF), and

High-dose IV and oral antibiotics were better than standard therapy in an Indonesian study.

adjunctive corticosteroids. High-dose rifampicin tripled plasma and CSF concentrations compared with those seen with the standard dose (p<0.0001 for both). Patients given 800 mg moxifloxacin had twice the plasma concentration of patients given 400 mg moxifloxacin and a 60 percent increase in CSF concentration (p<0.0001, p=0.006, respectively). The higher exposure to rifampicin in our study suggests a combination of a higher dose, intravenous administration, and nonlinear pharmacokinetics of this antibiotic,

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said, and the mortality was lower in the highdose rifampicin group 34 percent vs 65 percent in the standard therapy group. Moxifloxacin did not appear to affect mortality. Rifampicin is still an appealing drug for tuberculosis, especially in developing countries since it is cheap, accessible, well tolerated, and physicians are aware of it, Ruslami said, adding that defining the optimum regimen from such drugs could help control TB meningitis in areas of need.

the researchers said. Ruslami noted that TB meningitis is rare but can be severe and has high mortality; over 50 percent of patients die even when they complete treatment. In the current study, half of the patients died within 6 months, many within the first month, mostly due to respiratory failure and neurological deterioration. However, the rate of adverse events was no more than that of standard therapy, Ruslami

Rapid TB test performs well onsite

aboratory diagnosis of tuberculosis (TB) improved by 50 percent when a novel rapid DNA test was added to standard sputum smear microscopy. When used alone, the Xpert MTB/RIF rapid DNA test improved diagnosis by 41 percent compared with microscopy, according to data presented by the international group Medicines Sans Frontieres (MSF). Culture is the current gold standard for definitive TB diagnosis, but results can take up to 6 weeks. However, the Xpert test can return results within 2 hours. The rapid assay can also distinguish bacteria resistant to rifampicin, a first-line TB drug, as well as non-tubercular mycobacteria. For drug-sensitive TB, based on Xpert, people can be put on treatment, said Dr. Martina Casenghi, research advisor with MSFs Campaign for Access to Essential Medicines. For drug-resistant TB... in high multiple drug-resistant TB (MDR-TB) settings, you can start patients on an optimized regimen and then send them for a full drug sensitivity testing to tailor the regimen.

A new rapid TB diagnostic test has been rolled out in various locations around the world.

MDR-TB diagnosis in low-burden settings still necessitates a confirmatory culture for rifampicin resistance, she noted. The Xpert test is a semi-automated DNA assay in a closed system. A technician prepares a sputum sample with reagents in a car-

Photo credit: WHO

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had a relative gain of 50 percent in detection of TB, said presenter Dr. Elisa Ardizzoni of the Mycobacteriology Unit of the Institute of Tropical Medicine in Antwerp, Belgium. The data included a relatively large number of inconclusive results from Xpert, almost 7 percent among the whole data set. However, these decreased over the 18-month data gathering period as technicians became more skilled and new cartridges became available. Although the benefits of the Xpert test do not exclude the need for better point of care tests in peripheral, resource-poor settings, Casenghi said it is a step in the right direction to have a simple, fast test that returns good results in TB endemic countries without requiring extensive infrastructure.

tridge and loads it into the machine, which is about the size of a microwave. The machine costs US$17,000 and each cartridge costs US$10. The process limits contamination and returns fewer false-positive results as well as minimizing the skill set required to do diagnostic testing. The Xpert was rolled out in 25 locations around the world, including one site each in Vietnam and Myanmar. Some sites were in high burden MDR-TB locations, some used Xpert together with sputum culture or microscopy, some used Xpert alone and some reported results in children. The total number of samples was 36,540. When we added expert to microscopy we

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8th International Symposium on Respiratory Diseases and American Thoracic Society in China Forum, 8-11 November, Shanghai, China Chuah Su Ping reports

Interview with the Presidents

The 8th International Society for Respiratory Disorders (ISRD) annual meeting marked the inaugural joint scientific session between the ISRD and the American Thoracic Society (ATS). Medical Tribune spoke to the leadership of both organizations - Professor Chunxue Bai, president of the 8th ISRD and ATS in China Forum, and Dr. Monica Kraft, president of the ATS - to gain their views on key topics in respiratory diseases. MT: How will the updated Global Initiative for COPD (GOLD) guidelines affect current clinical practice? Kraft: The main difference is the criteria for diagnoses [of COPD]. Theyre quite different from previous versions and we are currently in an adjustment period trying to better understand how to best apply these guidelines in practice. The definitions of different severities of COPD have also changed. MT: How has respiratory clinical practice today evolved to improve quality of care for patients, in particular the use of telemedicine? Bai: This year we will be introducing delegates to what I like to refer to as the Medical Internet of Things, which is basically a combination of electronic medicine plus mobile health, or telemedicine. This has already started being implemented for patients being treated for sleep apnea [in China] and enables a doctor in a clinic or hospital to monitor a patient who is at home. The idea is for patients to take home a portable monitor and the data will be sent directly to
Professor Chunxue Bai Dr. Monica Kraft

the doctors office. In some cases, this data may enable doctors to make a preliminary diagnosis. Doctors are also able to feedback directly to patients via the internet upon receiving the results. This technology will allow data to be monitored and recorded while the patient is asleep at home, which is very useful in the diagnosis and treatment of sleep apnea. Kraft: I think telemedicine is still an evolving field, and I am still skeptical as to how it will be applied to clinical practice in the long term. This is an area we still need to explore in greater detail. MT: What do you think are the implications of the results from two early-phase clinical trials [NEJM 2012;366:2443-54, NEJM 2012;366:2455-65] presented at the 2012 ASCO meeting which provide further evidence on the role of the immune system in treating patients with NSCLC? Bai: I do believe the immune system plays an important role in lung cancer treatment. In China, there is ongoing research looking into the development of a vaccine for [non-

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of gene expression which are associated with response to specific chemo-therapeutic agents, as this can help us ensure patients are receiving the right combination of medication. In other words we are getting closer to the goal of personalized therapy in lung cancer.

small-cell lung cancer (NSCLC)]. However, at the end of the day, early diagnosis of lung cancer is key to extending patient survival. Kraft: Lung cancer remains a very challenging area, but I think weve made some progress in recent years. Its exciting that we have discovered specific biomarkers and patterns

Towards targeted COPD treatment

hronic obstructive pulmonary disease (COPD) treatment should be individualized based on each patients clinical phenotype, says an expert. To do so, we would need to move away from the traditional assessment of COPD and its treatment, said Professor Paul W. Jones, professor of respiratory medicine and head of the division of clinical science at St. Georges, University of London, UK. One of the key updates to the Global Initiative for COPD (GOLD) guidelines last year was when we categorized the treatment aims [for COPD] into two groups symptomatic benefit and risk reduction, said Jones, who is a member of the GOLD Science Committee. Symptomatic benefit includes relief of symptoms, improvement in exercise tolerance and health status whereas risk reduction includes prevention of exacerbations and disease progression, and reduction in mortality. This was a big step forward as we explicitly started to recognize that the manifestations of COPD differ between individual patients. In the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study, Hurst JR et al observed, over a 3-year period, that 71 percent of frequent exacerbators in years 1 and 2 were frequent ex-

acerbators in year 3, whereas, approximately 70 percent of patients who had no exacerbations in years 1 and 2 had no exacerbations in year 3. Thus, they concluded that the single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. [N Engl J Med 2010;363:1128-38] In this years GOLD [2012] update, we also recognize that hospitalization is a very important risk factor. If a patient has had one or more hospitalizations in a year, that automatically places them in a high-risk category, said Jones. In 1997, Jones and Bosh published a study in which they observed that the patients estimate of treatment efficacy correlated with changes in the St. Georges Respiratory Questionnaire (SGRQ) score. If the patients judged their treatment as ineffective, that correlated with a worse SGRQ score. However, if they judged their treatment as effective or very effective, the improvement in SGRQ score was either at the threshold of clinical significance or better, said Jones. [Am J Respir Crit Care Med 1997;155:1283-1289] These findings are significant as they tell us that the patients personal feedback should also be taken into consideration.

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long-acting beta agonist and long-acting muscarinic antagonist. [Thorax 2012;67:781-788] In treating COPD, one of the key things to remember is to treat, to improve the patients symptoms and reduce exacerbations, Jones said. Physicians can then customize treatment based on the patients clinical phenotype.

Highlighting a recent study by Mahler DA et al, Jones noted that when indacaterol was added to tiotropium, there was a significantly greater change in symptoms compared with patients on tiotropium alone. These results are in line with the COPD guideline recommendations to combine bronchodilators with different mechanism of actions, in this case a

NIPPV for treating COPD exacerbations

on-invasive positive pressure ventilation (NIPPV) is currently the preeminent established application in acute respiratory failure of chronic obstructive pulmonary disease (COPD) exacerbations, but experts say skilled application is critical for patient breathing. The rationale for selecting NIPPV is to first of all reduce the patients breathing workload, said Dr. Giuseppe A. Marraro, director of the Anesthesia and Intensive Care Department at the A.O. Fatebenefratelli and Ophthalmiatric Hospital in Milan, Italy, and this procedure can improve gas exchange, reduce endotracheal intubation, reduce infection rate and increase patient survival. [Lancet 2009;374:250] These are all key factors which will eventually determine treatment success in patients with COPD exacerbations. But he noted that patient collaboration and the skill of hospital staff can play a major role in how effective NIPPV will be. Compared with conventional ventilation, NIPPV confers a higher risk of mask dislodgment and there is a need for higher ventilator pressure, said Marraro. He highlighted that NIPPV is contraindicated in pa-

tients who require more than 50 percent oxygen; with significant hypotension induced by conventional ventilator therapy; with fractured skull base, facial fractures and increased intracranial pressure; and with respiratory arrest. Marraro cautioned that NIPPV should be discontinued if there is no improvement in gas exchange or dyspnea, or if there is a need for endotracheal intubation to manage secretions or protect the airway. Stop NIPPV immediately if the patient exhibits coordinative problems, reduced consciousness and increasing levels of carbon dioxide coupled with decreasing pH levels, he stressed. Patients with COPD who have exacerbations of respiratory failure can benefit significantly from ventilator assistance. NIPPV has been shown to reduce the severity of breathlessness within the first four hours of treatment, decrease the length of hospital stay and reduce the rates of mortality and intubation, said Marraro. He noted that the advantages of NIPPV include the avoidance of intubation, which is typically necessary for 16-35 percent of acute COPD exacerbations and carries its own complica-

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it, and ingest orally. The facial mask on the other hand, may be more useful for dyspneic patients who are usually mouth breathers, said Marraro. NIPPV can be applied in appropriate non-ICU settings but it is important to take into consideration the patients personal feedback as well as the need for fully trained and experienced hospital staff and appropriate equipment, monitoring and support.

tions. NIPPV preserves the patients ability to cough, speak and swallow. It can also be used away from the ICU, thereby potentially reducing costs. With NIPPV, physicians have the choice of selecting either a nasal or facial mask for their patients. The advantages of the nasal mask are that it is less claustrophobic and allows the patient to speak, expectorate, vom-

OSA linked to glucose dysmetabolism

ccumulating evidence suggests that obstructive sleep apnea (OSA) is associated with glucose dysmetabolism, says an expert. While the link remains controversial, it is clear that both conditions are related to obesity, said Professor Mary Ip of the University of Hong Kong. OSA may also have a causal role on increasing insulin resistance, glucose tolerance and type 2 diabetes mellitus [T2DM]. There have been many studies examining the relationship between insulin resistance and OSA, but few studies on the role of B-cell dysfunction in OSA, noted Ip. One such study by Punjabi NM et al showed that severe OSA is associated with impaired Bcell dysfunction. [Am J Respir Crit Care Med 2009;179:235-240] This reduces the compensatory insulin secretion, leading to the development of glucose intolerance or diabetes, said Ip. In the Sleep Heart Health Study, Seicean S et al found that OSA may be independently associated with various states of glucose metabolism including impaired fasting glucose,

CPAP has been shown to improve insulin sensitivity in non-diabetic patients.

impaired glucose tolerance and occult diabetes. [Diabetes Care 2008;31:1001-1007]

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Many studies have been carried out to examine the effect of CPAP treatment of OSA in patients with T2DM, however, most did not report any significant difference on glycemic control [post-treatment], she said. Compliance to CPAP may also play an important role in improving insulin resistance in OSA patients. The use of CPAP to improve insulin sensitivity in OSA patients remains to be validated. While convincing data demonstrate a link between OSA and B-cell dysfunction, insulin resistance, metabolic syndrome and increasing HbA1c levels, little is known about the long-term outcomes of OSA treatment for T2DM, which Ip said would be a key area for future research.

Similarly, a study in Hong Kong showed that OSA was independently associated with metabolic syndrome, hypertension and [increased] waist circumference, said Ip. [Respir Med 2006;100:980-987] More recent studies in Japan and China have also shown that patients with severe OSA had a higher prevalence of hypertension, dyslipidemia, glucose intolerance and metabolic abnormalities. [Respirology 2010;15:1122-1126, Sleep Breath 2012;16:571-578] Continuous positive airway pressure (CPAP) treatment for OSA has been shown to improve insulin sensitivity in non-diabetic patients with BMI less than 30 kg/m2. [Am J Respir Crit Care Med 2004;169:152-62] However, the effects of CPAP treatment in patients with T2DM remains controversial, Ip said.

CPAP may improve cognitive function in OSA patients

ontinuous positive airway pressure (CPAP) treatment for obstructive sleep apnea (OSA) may improve neurocognitive function, show the latest results from the Apnea Positive Pressure Long-Term Efficacy Study (APPLES). Up till recently, there have been studies examining the effect of sleep apnea on neurocognitive function said Professor Clete A. Kushida of Stanford University Medical Center in Stanford, California, US. Previous studies, however, have been limited by relatively small sample sizes, noncomprehensive test batteries and inadequate control groups. [J Clin Sleep Med 2006;2:288-300] In APPLES, Kushida and his team random-

ized 1,100 OSA patients to receive either active CPAP or its sham version to test the hypotheses that hypoxemia and/or sleepiness in OSA is responsible for neurocognitive decline. The main aims of the study were to identify specific deficits in neurocognitive function in a large heterogenous population of OSA patients and to assess the long-term effectiveness of CPAP therapy on neurocognition, mood, sleepiness and quality of life. It also sought to evaluate which deficits are reversible and most sensitive to the effects of CPAP. [J Clin Sleep Med 2006;2:288-300] The primary outcomes examined were attention and psychomotor function; learning and memory (L/M); and executive and

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Interpreting APPLES The detection of CPAP effects in the primary E/F variable suggests that the SWMT test - in which a cognitive task is combined with simultaneous electroencephalographic measures of brain function - is a more sensitive measure for subtle neurocognitive changes, said Kushida. The mixed results from prior studies, as well as the limited effect on CPAP on neurocognition in APPLES, suggest the existence of a complex OSA-neurocognitive relationship. Clinicians should consider disease severity, sleepiness, individual differences (variability in neurocognitive function and brain reserve) and treatment adherence in managing OSA patients with CPAP, he opined. Lastly, we need more large-scale sleep studies to further examine the efficacy or inefficacy of CPAP therapy on this very prevalent sleep-related breathing disorder. The results of APPLES are expected to be published in December 2013.

frontal-lobe function (E/F). These were examined via the Pathfinder Number (PN) Test, the Buschke Selective Reminding Test (BSRT), and the Sustained Working Memory Test (SWMT), respectively, said Kushida, who is also president of the World Sleep Federation. While covariate-adjusted analyses revealed no significant differences in the PN and BSRT test results between the active CPAP and sham group, we did find significantly better SWMT results, which examined E/F, in the active CPAP group, he said. Lower levels of oxygen saturation and increased sleepiness also produced significant effects on the E/F test. However, these effects were only detected at 2 months and were minor compared with the effects of caffeine and diphenhydramine for this measure in other studies, he noted. Interestingly, the study also reported that adherence to CPAP was significantly lower in the sham group, and this, said Kushida, was a major limitation in APPLES.

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Personal Perspectives

In developing the new GOLD guidelines, we set clear treatment objectives based on improving symptoms; and for the first time in COPD, identifying that risk reduction is a key component in treatment, particularly in terms of reducing the risk of exacerbations. Paul W. Jones, University of London, UK

One of the things we need to do is to strengthen the bridge between Eastern and Western science. Meetings like these not only showcase the science being done here in China but also facilitate the exchange of ideas to advance the state of the science globally. As an economist, my interest lies mainly in the cost-of-care issues of access and delivery systems. Stephen Crane, Executive Director, American Thoracic Society

The topics of any conference should first of all reflect the prevalence of the disorders in the [host] country. Sleep apnea, lung cancer and COPD are all prevalent in China. Second, it should also reflect the emerging science which will affect treatment and diagnosis. Third, it should support ongoing research within the country. Lastly, it should also define what the young physicians will be facing in the future. In my opinion, the ISRD 2012 has done an excellent job in bringing all that together. Teofilo Lee-Chiong, University of Colorado, US

Being an international conference with delegates attending from all over the world, there should be more English speaking staff on hand. Every time we need any help, we have to go the secretariat office. Other than that, everything else was great. Maulik Sanghvi, India

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Gastroesophageal Reflux Disease

Once weekly exercise enough to reduce GERD risk in obese

Rajesh Kumar
bese individuals can reduce their risk of developing gastroesophageal reflux disease (GERD) by exercising even if only once-a-week, according to a Swedish study. However, no such benefit from occasional physical activity was seen in patients with normal body mass index (BMI). [World J Gastroenterol 2012;28:3710-3714] Researchers randomly selected 4,910 people aged between 40 and 79 years from the Swedish registry of the total population for a cross-sectional survey. Data on their physical activity, GERD, BMI and the covariates age, gender, comorbidity, education, sleeping problems, and tobacco smoking were obtained using validated questionnaires. GERD was self-reported and defined as heartburn or regurgitation at least once weekly, and the presence of at least moderate problems from such symptoms. Frequency of physical activity was categorized into high (several times/week), intermediate (approximately once weekly) and low (1-3 times a month or less). Analyses were stratified for participants with normal weight (BMI < 25 kg/m2), overweight (BMI 25 to 30 kg/m2) and obese (BMI > 30 kg/m2). Obese participants were on average slightly older, had fewer years of education, more comorbidity, slightly more sleeping problems, lower frequency of physical activity, and higher occurrence of GERD. In 680 obese individuals, intermediate frequency of physical activity was associated with a decreased occurrence of GERD com-

pared with low physical activity (adjusted hazard ratio [HR] 0.41). Among the 2,146 normal-weight participants, a decreased risk of GERD was seen with higher physical activity (HR 0.59), but the benefit was negated after adjusting for potential cofounders such as sleeping problems and high comorbidity. A similar trend was seen in 1,859 overweight participants. The studys limitations include an inherent uncertainty about the accuracy of self-reported data and lack of validation of the assessment of frequency of physical activity, BMI and possible previous surgical interventions for GERD, said the study authors. Because it is a cross-sectional study, it is not possible to know if the participants with a self-detected association between reflux and physical exercise may have changed their behavior, resulting in reverse causality, they said. The current findings confirm the previous population-based studies assessing an association between physical activity and GERD within the general population. However, none of the previous studies stratified analyses for BMI categories; meaning that the decreased risk of GERD limited to obese individuals is a first time observation, said authors Dr. Therese Djrv and colleagues at the department of molecular medicine and surgery, Karolinska Institutet in Stockholm, Sweden. Should the present results be confirmed in future research, the findings from this study might be important for the prevention and treatment of GERD and its complications, they concluded.

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Gastroesophageal Reflux Disease

Barretts esophagus linked to type 2 diabetes

Alexandra Kirsten

retrospective study has shown that patients with type 2 diabetes have twice the risk of Barretts esophagus, a condition where the esophageal lining becomes abnormal, whether or not other risk factors such as smoking or obesity were present. The findings were presented during the American College of Gastroenterologys 77th Annual Scientific Meeting, held recently in Las Vegas, Nevada, US. [Abstract 49] To determine whether there is an association between type 2 diabetes and Barretts esophagus, Dr. Prasad Iyer, associate professor of gastroenterology and hepatology at the Mayo Clinic College of Medicine in Rochester, Minnesota, US, and his fellow researchers conducted a population-based, case-control study. They identified 14,245 patients with Barretts esophagus and 70,361 control subjects who were matched for age, sex, enrolment date, duration of follow-up, and practice region using the United Kingdoms General Practice Research Database, a primary care database that includes over 8 million patients. The data showed that patients with Barretts esophagus were more likely to have smoked and consumed alcohol, had a higher body mass index, and a higher prevalence of type 2 diabetes than control subjects. Multivariate analysis showed a 49 percent increased risk for Barretts esophagus in patients with type 2 diabetes. The link was stronger in men (OR, 2.03; 95% CI, 1.01 - 4.04) than in women (OR, 1.37; 95% CI, 0.63 - 2.97).

Patients with Barretts esophagus were also more likely to have smoked or consumed alcohol, and had a higher mean BMI than controls.

Interestingly, we found that among the study cohort, if you had diabetes there was a twofold increase in your risk for Barretts esophagus, Iyer said. When we stratified the results by gender, the association of type 2 diabetes with Barretts esophagus was stronger in males compared to females, which may reflect the different fat distributions in men and women. There is some evidence that central obesity is a risk factor for Barretts esophagus and esophageal cancer through mechanical or metabolic mechanisms, such as hyperinsulinemia. The researchers suggested fat in the abdomen could be a reflux-independent mechanism leading to Barretts esophagus which is known to be a precursor of esophageal adenocarcinoma. If we find the precursor early enough, we could put these patients under surveillance or treat the precursor and reduce the risk, Iyer said. He added that further prospective studies are needed to better understand the link between Barretts esophagus and type 2 diabetes.

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News

Health impact of open-fire cooking to be studied

Alexandra Kirsten

oxic smoke and soot from openfire cooking causes nearly 2 million deaths each year, primarily among women and children who spend the most time at fireside, according to the World Health Organization. To examine the link between the atmosphere and human health, the US National Center for Atmospheric Research (NCAR) in Boulder, Colorado, US, is launching a largescale study into the impact of open-fire cooking on regional air quality and disease. Pollutants and particles spewed by open fires are a proven health risk to individuals, to villages and entire regions, explained NCAR lead scientist Dr. Christine Wiedinmyer. The 3-year study will be the first to discuss broadscale solutions to disease and pollution from open-fire cooking The use of wood, animal and agricultural waste for cooking and warming homes in developing countries is a principal source of carbon monoxide, particulates and smog. These can cause a variety of symptoms, ranging from headaches and nausea to conditions like cardiovascular and respiratory diseases. The international team of pollution, climate, and health experts from NCAR, the University of Colorado Boulder, the University of Ghana School of Public Health and Ghana Health Services, will analyze the effects of smoke from traditional cooking methods on households, villages, and entire regions.

The large-scale study will also assess the potential of low-emission cook stoves to reduce disease.

Given that an estimated 3 billion people worldwide are cooking over fire and smoke, we need to better understand how these pollutants are affecting public health as well as regional air quality and even the climate, said Wiedinmyer. The research group will focus on determining the influence of traditional cooking methods on human health using air quality sensors and computer and statistical models. They will also evaluate the disease reduction capacity of low-emission cook stoves and if these newer, more efficient stoves positively affect regional air quality. Surveys among villagers on their understanding of the connection between open-fire cooking and disease will also help gauge their interest in changing their cooking habits. The results of the study could point to the best means for a transition to cleaner cooking methods and show how the open-fire emissions are affecting weather patterns that contribute to global warming.

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January 2013

News

Elderly face higher hip fracture risk after starting BP drugs

Rajesh Kumar

lderly hypertensive patients may be at higher risk of hip fractures in the first 45 days after starting antihypertensive drug therapy, according to research. Canadian researchers linked a cohort of 301,591 newly treated hypertensive rest home residents (mean age, 81 years) to the records of 1,463 hip fractures between 1 April 2000 to 31 March 2009. They analyzed the risk during the first 45 days following therapy initiation, with equal control periods before and after that and a total of 450-day observation period. [Arch Intern Med 2012; doi:10.1001/2013. jamainternmed.469] The outcome was the first occurrence of a proximal femoral fracture during the risk period. The researchers found a 43 percent increased risk of having a hip fracture during the risk period compared with the control periods (incidence rate ratio [IRR], 1.43; 95% confidence interval [CI], 1.19 to 1.72). Initiating antihypertensive drugs such as thiazide diuretics, angiotensin II converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs) or calcium channel blockers in the elderly is already associated with an immediate increased risk of falls. The study sought to find out the immediate risk of hip fracture. Adjusting for age and use of other medications implicated in falls, such as psychotropic drugs, did not change the risk. The relationship was generally consistent for all classes of antihypertensive drugs (IRRs, 1.30 to 1.58), although it reached statistical significance only

for ACE inhibitors (IRR, 1.53, 95% CI, 1.12 to 2.10) and -blockers (IRR, 1.58, 95% CI, 1.01 to 2.48). Dr. Kenneth Ng Kwan Chung, cardiologist at Novena Heart Centre in Singapore, said physicians know that ACE inhibitors can cause first dose hypotension, especially in patients who are already on diuretics. But it is not clear why -blockers were also implicated in the study. Elderly patients are more likely to have sick sinus syndrome and -blockers may cause severe bradycardia and then fainting and falls [leading to fracture], explained Ng. Asian patients are usually frailer and smaller sized than their Western counterparts, which might make the effect of antihypertensive medications more marked in them, he said, adding that physicians should start with the lowest possible dose of one medication and first check for postural hypotension, particularly when starting ACE inhibitors and -blockers in elderly patients. Check the heart rate before starting -blockersand educate the patient to get up slowly out of the bed or chair. Wait for any giddiness or instability to subside before taking the next few steps to walking. Ask a family member to watch over them when they get up in the middle of the night, said Ng. Patients could also monitor their blood pressure at home and send the readings to their family doctor, who can then advise them on the dose reduction or discontinuation of the medication if the blood pressure goes too low, he concluded.

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News

CABGmore effective than PCI in older CAD patients

Rajesh Kumar

n patients with multivessel coronary artery disease, coronary artery bypass graft (CABG) surgery was more effective in an older cohort, while percutaneous coronary intervention (PCI) was favored in a relatively younger one in a large analysis. Researchers pooled individual data from 7,812 patients who were randomized in 10 clinical trials of CABG or PCI to assess whether patient age modifies the comparative effectiveness of those interventions. [J Am Coll Cardiol 2012; 60:2150-2157] They analyzed age as a continuous variable in the primary analysis and divided it into three groups of 56.2 years, 56.3 to 65.1 years and 65.2 years for descriptive purposes. The outcomes assessed were death, myocardial infarction and repeat revascularization over complete follow-up and angina at 1 year. Older patients were more likely to have hypertension, diabetes, and 3-vessel disease compared with younger patients (p=0.001 for trend). Over a median follow-up of 5.9 years, the effect of CABG versus PCI on mortality varied according to age (interaction p=0.01), with adjusted CABG/PCI hazard ratios and 95 percent confidence intervals of 1.23 (95% CI 0.95 to 1.59) in the youngest group; 0.89 (95% CI 0.73 to 1.10) in the middle group; and 0.79 (95% CI 0.67 to 0.94) in the oldest group. The CABG/PCI hazard ratio was less than 1 for patients 59 years. A similar interaction of age with treatment was present for the composite outcome of death or myocardial infarction. In contrast, patient age did not alter the comparative effectiveness of CABG and PCI on the outcomes of repeat revascularization or angina.

Researchers analyzed pooled data from 10 clinical trials involving patients who had undergone CABG or PCI.

Dr. Kenneth Ng Kwan Chung, cardiologist at Novena Heart Centre in Singapore, said increasing age is known to be a risk factor for mortality and complications resulting from CABG. Therefore in patients who are elderly, we sometimes attempt to perform PCI on the stenotic lesions rather than send them for surgery. However, this study points out that the older patients actually benefit more from CABG than PCI. It could be that older patients have more diffuse disease than younger patients. Ng said the findings are relevant for Asians as we have a higher proportion of patients who are diabetic, compared with Caucasians, and have a rapidly aging population in which ischemic heart disease is the biggest cause of morbidity. The take home message for us is to explain to the patients aged >59 years that CABG could be a better option than PCI if they have triple vessel disease and diabetes. This is because of a 21 percent lower risk of cardiovascular mortality in the >65 years age group in the study, he said. Also, there was no difference in complications between the PCI and CABG groups in terms of death from the procedure and stroke.

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January 2013

News

Bleeding rates with warfarin much higher in reality?

Elvira Manzano
he rates of major bleeding with warfarin use in atrial fibrillation (AF) may be higher than reported in clinical trials and are often fatal, new research suggests. A population-based study conducted in Canada involving 125,195 patients who started warfarin therapy after a diagnosis of AF showed an overall rate of hemorrhage of 3.8 percent per person-year over a study period of 13 years. The risk of major hemorrhage (defined as a visit to an emergency department or admission to hospital) was highest during the first 30 days of treatment (11.8 percent per person-year). [CMAJ 2012;doi:10.1503/ cmaj.121218] The results were important as they reflect the bleeding rates with warfarin in the real world, said lead study author Assistant Professor Tara Gomes, of the University of Toronto in Ontario. These rates are considerably higher than the rates of 1 to 3 percent per person-year reported in randomized controlled trials of warfarin therapy. The difference, she said, may be due to the strict inclusion criteria and close monitoring of patients in clinical trials and the average age of participants in their study being older. Warfarin helps prevent stroke and blood clots in AF patients. However, it has a narrow therapeutic window (international normalized ratio [INR] 3-4) and requires regular monitoring to minimize the risk of hemorrhage. Currently, there are no large trials offering real-world, population based-estimates of bleeding rates among patients on warfarin.

Real-life bleeding rates associated with warfarin may be much higher than those reported in clinical trials.

This prompted Gomes and colleagues to study the medical records of AF patients (aged 66 years or older) who started warfarin therapy between April 1997 and March 2008. The cumulative incidence of hemorrhage was 4.1 percent at 1 year and 8.7 percent at 5 years. In total, 1,963 patients (18.1 percent) died in the hospital or a week after discharge. Although the rate of intracranial hemorrhage was low in the study, it was associated with a high mortality rate (42 percent). As expected, bleeding rates were higher in those with a CHADS2 score of 4 or higher (16.7 percent per person-year) and in patients older than 75 years (4.6 percent per person-year). Our study provides timely estimates of warfarin-related adverse events that may be useful to clinicians, patients and policymakers as new options for treatment become available, Gomes said. Doctors should know the potential for bleeding in patients when starting them on warfarin. However, the decision to shift to new oral anticoagulants could not be made on the basis of these data alone, she said.

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January 2013

News

Digoxin linked to raised mortality risk in patients with AF

Rajesh Kumar

hysicians should reassess the role of digoxin in the management of atrial fibrillation (AF) in patients with or without heart failure (HF), experts warned following study findings that link the drug to a significant increase in mortality in such patients. Digoxin is widely used around the world for the treatment of AF and HF. It is extracted from the foxglove plant (digitalis) and helps the heart beat stronger and have a more regular rhythm. However, it has a narrow therapeutic index beyond which it can be dangerous. Researchers analyzed data from 4,060 AF patients who had enrolled in the landmark AFFIRM* trial to determine the relationship between digoxin and deaths in this group. [Eur Heart J 2012; doi:10.1093/eurheartj/ehs348] Digoxin was associated with a 41 percent increase in all-cause mortality (estimated hazard ratio [EHR], 1.41, 95% confidence interval (CI), 1.19 to 1.67, p<0.001], 35 percent increase in cardiovascular mortality (EHR, 1.35, 95% CI, 1.06 to 1.71, p=0.016), and 61 percent increase in arrhythmic mortality (EHR, 1.61, 95% CI, 1.12 to 2.30, p=0.009). The all-cause mortality was increased in patients with or without HF (EHR, 1.37, 95% CI, 1.05 to 1.79, p=0.019 and EHR 1.41, 95% CI 1.09 to 1.84, p=0.010, respectively). The higher mortality remained even after controlling for other medications and risk factors, and regardless of gender. In view of these findings, we should try to control a patients heart rate by using

alternatives to digoxin as a first-line, such as -blockers or calcium channel blockers, said co-researcher Dr. Samy Claude Elayi, associate professor of medicine at the Gill Heart Institute, University of Kentucky in Lexington, Kentucky, US. And if digoxin is used, use a low dose with careful clinical follow-up, evaluate potential drug interactions when starting new medications, and monitor plasma digoxin levels, added Elayi. Patients should be aware of potential toxicity and see their physicians immediately in specific clinical situations, for instance if they experience palpitations or syncope, as those may precede arrhythmic death, he cautioned. Until now, there have been limited data on the use of digoxin in AF patients as it has scarcely been studied in these patients. The main prospective randomized controlled trials involving the drug were performed in patients with HF and sinus rhythm, excluding those with AF, said the researchers. The mechanism by which the drug increases deaths among patients is unclear. Mortality from classic cardiovascular causes, whether due to arrhythmia or not, can partly but not entirely explain it. This suggests there must be some additional mechanism that remains to be identified, they added. There is a need for further studies of the drugs use, particularly in systolic HF and AF patients that would, in theory, benefit the most from digoxin, concluded Elayi.
*AFFIRM: Atrial Fibrillation Follow-up Investigation of Rhythm Management

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January 2013

Research Reviews

Devices to remove thrombus in acute ischemic stroke

reatments for acute ischemic stroke include use of IV recombinant tissue plasminogen activator (rt-PA), intra-arterial fibrinolysis and the use of mechanical clot-removing devices. Two new clot-removing devices have been compared with a currently used device (the Merci Retriever) in successively reported studies in the Lancet. The Merci retriever is a flexible nitinol wire with distal corkscrew-shaped coil loops with attached filaments. It is placed distally to the clot to ensnare and remove the clot into a balloon-guide catheter in the cervical internal carotid or vertebral arteries. The Trevo Retriever is a new device, a stent retriever which is placed via a microcatheter. The stent is opened and the clot is trapped in the stent struts and retrieved into an internal carotid or vertebral artery catheter. A trial at 26 sites in the US and one in Spain included 178 patients with large-vessel occlusion acute ischemic stroke. Randomization was to thrombectomy with one or other of the two devices. A thrombolysis in cerebral infarction (TICI) score of 2 or greater reperfusion was achieved in 86 percent of patients with the Trevo Retriever and 60 percent with the Merci Retriever, showing the superiority of the Trevo Retriever. Device safety was similar in the two groups. The Solitaire Flow Restoration Device is also a self-expanding stent retriever. A trial at 18 US sites and one in France included 113 patients. A thrombolysis in myocardial infarction (TIMI) score of 2 or 3 was achieved in 61 percent (Solitaire) vs 24 percent (Merci), showing superiority of the Solitaire device. A good neurological outcome at 3 months was recorded for 58 percent vs 33 percent, and 90-day mortality was 17 percent vs 38 percent. The Trevo and Solitaire devices were both better than the Merci device.
Nogueira RG et al. Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial. Lancet 2012; 380: 123140; Saver JL et al. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised parallel-group, non-inferiority trial. Ibid: 12419; Gorelick PB. Assessment of stent retrievers in acute ischaemic stroke. Ibid: 120810 (comment).

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January 2013

Research Reviews

Predicting CV risk with C-reactive protein, fibrinogen levels

here is debate about the usefulness of measuring C-reactive protein and fibrinogen levels in healthy people to predict risk of cardiovascular disease. An analysis of 52 prospective studies (n=246,669 participants) without known cardiovascular disease has been reported. It was estimated that the addition of C-reactive protein or fibrinogen to standard risk factors would improve the classification of people into low, intermediate or high 10-year risk categories by 1.52 percent and 0.83 percent, respectively. With appropriate use of statin therapy, the addition of C-reactive protein and fibrinogen measurements might prevent 30 cardiovascular events over 10 years among 100,000 adults aged 40 years or older. It is concluded that with current treatment guidelines, C-reactive protein or fibrinogen measurement in people at intermediate cardiovascular risk could help prevent one additional event over a period of 10 years for every 400 or 500 people screened.
The Emerging Risk Factors Collaboration. C-reactive protein, fibrinogen, and cardiovascular disease prediction. NEJM 2012; 367: 131020.

Prasugrel vs clopidogrel for ACS without revascularization

here is uncertainty about optimum platelet inhibition therapy for patients with unstable angina or non-ST-segment elevation myocardial infarction (non-STEMI) who are managed without revascularization. A study at 966 sites in 52 countries has shown similar results with either prasugrel or clopidogrel. A total of 7,243 patients aged <75 years were randomized to take either prasugrel 10 mg daily or clopidogrel 75 mg daily, in addition to aspirin, for up to 30 months. After an average follow-up of 17 months the primary end-point (cardiovascular death, myocardial infarction or stroke) was reached by 13.9 percent (prasugrel) vs 16.0 percent (clopidogrel), a nonsignificant difference. Further analysis of multiple ischemic events suggested a lower risk with prasugrel (a significant 15 percent reduction). Heart failure was more frequent in the clopidogrel group. Otherwise, the rate of adverse events was similar in the two groups. Prasugrel did not reduce the frequency of the primary endpoint significantly compared with clopidogrel.
Roe MT et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularisation. NEJM 2012; 367: 1297309.

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January 2013

Research Reviews

Perioperative and anesthetic-related deaths: Systematic review, meta-analysis

systematic review and meta-analysis has assessed changes in perioperative mortality in developed and developing countries over the last 3-4 decades. The study included 87 studies with information about 21.4 million administrations of general anesthesia for surgery. Mortality due solely to anesthesia was 375 per million before the 1970s, 52 per million in the 1970s and 80s, and 34 per million in the 1990s and 2000s. The corresponding figures for total perioperative mortality were 10,603, 4,533, and 1,176 per million. The United Nations Human Development Index (HDI), which is based on life expectancy, literacy, further education and income, was used to assess the development status of countries. There was a significant relationship between HDI score and perioperative and anesthetic-related mortality. Rates of anesthetic-related mortality fell significantly in high-HDI (developed) countries but rose in low-HDI (developing) countries. Total perioperative mortality decreased in both high and low HDI countries but the decrease was slower in low HDI countries. Rates of cardiac arrest were higher in low HDI countries. Despite an increase in the number of greater risk patients being operated on, the perioperative mortality has decreased significantly over the last few decades but the decrease has been slower in developing countries. More attention needs to be given to increasing evidence-based best practice in developing countries.
Bainbridge D et al. Perioperative and anaesthetic-related mortality in developed and developing countries: a systematic review and meta-analysis. Lancet 2012; 380: 107581; Avidan MS, Kheterpal S. Perioperative mortality in developed and developing countries. Ibid: 10389 (comment).

Tranexamic acid and death from traumatic bleeding

ranexamic acid given within 3 hours of injury reduces mortality in patients with traumatic bleeding. An analysis of data from an international randomized trial has shown that the benefit from tranexamic acid does not vary with the severity of injury. The trial included 13,273 patients randomized to tranexamic acid or placebo within 3 hours of injury and stratified according to risk of death at baseline (<6 percent, 6-20 percent, 21-50 percent, or >50 percent). In these risk strata, the reduction in risk of death with tranexamic acid was 37, 29, 32 and 28 percent, respectively, with no significant difference between strata. Treatment with tranexamic acid reduced the risk of arterial, but not venous, thrombosis. Tranexamic acid given within 3 hours of injury reduces mortality from bleeding at all degrees of severity of injury.
Roberts I et al. Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial. BMJ 2012; 345 (Oct 6): 16 (e5839).

42

January 2013

Research Reviews

MRI abnormalities in radiologically normal knees

any people with knee pain have no abnormality on knee X-rays. A US study has shown that MRI in these circumstances may show abnormalities of questionable clinical significance. The study, in the Framingham community cohort, included 710 people aged >50 with normal knee X-rays. Knee pain in the last month was reported by 206 people (29 percent). An osteoarthritic abnormality was detected by MRI in 631 subjects (89 percent); 524 (74 percent) had osteophytes, and 492 (69 percent) cartilage damage. The frequency of abnormalities increased with age. The prevalence of abnormalities was 90 to 97 percent among subjects with knee pain and 86 to 88 percent among those without knee pain. Osteoarthritic abnormalities on MRI are common after the age of 50 whether or not the subject complains of knee pain and are therefore of questionable clinical significance.
Guermazi A et al. Prevalence of abnormalities in knees detected by MRI in adults without knee osteoarthritis: population based observational study (Framingham Osteoarthritis Study) BMJ 2012; 345 (Sept 15): 16 (e5339).

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43

January 2013

Research Reviews

Hyperglycemia and hypoglycemia in critically ill patients

evere hyperglycemia in patients in the intensive care unit (ICU) is associated with increased mortality. Initial reports suggested that careful control of blood glucose levels might reduce this mortality but these findings have not been confirmed in more recent trials. The Normoglycaemia in Intensive Care Evaluation-Survival using Glucose Algorithm Regulation (NICE-SUGAR) trial, reported in 2009, showed increased mortality with intensive glucose control. Other evidence has suggested that hypoglycemia may be the underlying factor. Now a further analysis of data from the NICE-SUGAR trial has demonstrated a relationship between moderate or severe hypoglycemia and mortality. The NICE-SUGAR study included 6,104 adults in ICUs in 42 hospitals. The present analysis is of follow-up data for 6,026 patients among whom 45 percent had moderate hypoglycemia (blood glucose 2.33.9 mmol/L) and 3.7 percent had severe hypoglycemia (2.2 mmol/L or less). Moderate hypoglycemia occurred in 74 percent of patients in the intensive blood glucose control group and severe hypoglycemia in 7 percent. Most episodes of severe hypoglycemia (93 percent) occurred in the intensive control group. Mortality was 28.5 percent among patients with moderate hypoglycemia, 35.4 percent among those with severe hypoglycemia, and 23.5 percent among those who did not develop hypoglycemia, giving 41 percent and 2.1-fold increase in risk with moderate and severe hypoglycemia. The risk of death was particularly increased in patients who had moderate hypoglycemia on more than 1 day, those who had severe hypoglycemia without insulin treatment, and those who developed distributive (vasodilated) shock. Intensive glucose control in ICU patients commonly causes moderate or severe hypoglycemia with an increased risk of death but these data cannot prove a causal relationship between hypoglycemia and death. A target blood glucose of 8.0-10.0 mmol/L for ICU patients is recommended by the American Diabetes Association.
The NICE-SUGAR Study investigators. Hypoglycemia and risk of death in critically ill patients. NEJM 2012; 367: 110818; Hirsch IB. Understanding low sugar from NICE-SUGAR. Ibid: 11502 (editorial).

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January 2013

Research Reviews

Tiotropium for poorly controlled asthma

hree studies have shown benefit from the addition of tiotropium, a long-acting anticholinergic bronchodilator, to inhaled steroid and long-acting beta-agonist, in the treatment of poorly controlled asthma. These studies, however, have only lasted for 8 to 16 weeks and longer-term studies are needed. Two multinational 48-week replicate studies have been reported together. The trials included a total of 912 patients (mean age 53 years) with asthma poorly controlled on standard treatment who were randomized to inhaled tiotropium 5.0 mg or placebo every morning for 48 weeks. At 24 weeks the mean increase in peak FEV1 from baseline was significantly greater in the tiotropium group in both trials (86 mL in trial 1 (n=459 patients) and 154 mL in trial 2 (n=453). The increase in trough FEV1 was also significantly greater in the tiotropium group in both trials. The time to first severe exacerbation was 282 days (tiotropium) vs 226 days (placebo) and the risk of severe exacerbations was reduced by 21 percent with tiotropium. Adverse events were similar in the two groups. The addition of tiotropium was beneficial for patients with asthma poorly controlled on inhaled steroid and long-acting beta-agonist.
Kerstjens HAM et al. Tiotropium in asthma poorly controlled with standard combination therapy. NEJM 2012; 367: 1198207; Bel EH. Tiotropium for asthma promise and caution. Ibid: 12579 (editorial).

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January 2013

Research Reviews

Coronary stents for patients with diabetes

here is controversy about the relative merits of various coronary stents for use in patients with diabetes. Paclitaxel-eluting, sirolimus-eluting, and everolimus-eluting stents have each been advocated. A meta-analysis has favored everolimus-eluting stents. The analysis included 42 trials and 22,844 patient-years of follow-up. All currently used drug-eluting stents were associated with a decreased risk of target vessel revascularization among patients with diabetes compared with bare metal stents. Everolimus-and sirolimuseluting stents were similar in efficacy and better than paclitaxel- or zotarolimus-eluting stents. The median target-vessel revascularization rate was 109 per 1000 patient-years with bare metal stents and 35 per 1000 patient-years with everolimus-eluting stents. There was a 62 percent probability that everolimus-eluting stents were the safest with the lowest rate of any stent thrombosis. Among patients with diabetes, drug-eluting stents are more effective than bare-metal stents without compromising safety. Everolimus-eluting stents may be the best choice. A BMJ editorialist questions the cost-effectiveness of drug-eluting stents for patients with diabetes and maintains that optimal medical treatment will probably remain the core treatment for patients with diabetes.
Bangalore S et al. Outcomes with various drug eluting or bare metal stents in patients with diabetes mellitus: mixed treatment comparison analysis of 22,844 patient years of follow-up from randomised trials. BMJ 2012; 345: (Sept 22): 16 (e5170); Mak K-H. Drug eluting stents for patients with diabetes. Ibid: 7 (e5828) (editorial).

Intra-aortic balloon support after acute MI: not beneficial

ntra-aortic balloon counterpulsation is widely used for patients with acute myocardial infarction (MI) and cardiogenic shock and it is recommended in US and European guidelines, but there is a paucity of good evidence to support its use. Now a multicenter study in Germany has shown no significant reduction in 30-day mortality. A total of 600 patients with cardiogenic shock and acute MI who were awaiting early revascularization were randomized to intra-aortic balloon counterpulsation (IABP) or a control group. At 30 days, mortality was 39.7 percent (IABP) vs 41.3 percent (controls), a nonsignificant difference. There were no significant differences between the groups in time to hemodynamic stabilization, length of stay in intensive care, serum lactate levels, dose or duration of catecholamine therapy, renal function, major bleeding, peripheral ischemic complications, sepsis, or stroke. Intra-aortic balloon counterpulsation was not significantly effective.
Thiele H et al. Intraaortic balloon support for myocardial infarction with cardiogenic shock. NEJM 2012; 367: 128796; OConnor CM, Rogers JG. Evidence for overturning the guidelines in cardiogenic shock. Ibid: 134950 (editorial).diabetes. Ibid: 7 (e5828) (editorial).

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January 2013

Research Reviews

Blood pressure control in diabetes

t is often assumed that achieving a low blood pressure is a valid aim for patients at high cardiovascular risk, but data from the UK General Practice Research Database have suggested that too low a blood pressure may also be harmful. Data were analyzed for 126,092 adults with newly diagnosed type 2 diabetes between 1990 and 2005. Almost 10 percent (9.8 percent) of the patients had had a myocardial infarction or stroke before the diagnosis of diabetes. During an average follow-up of 3.5 years, mortality was 20 percent. Among subjects with cardiovascular disease, blood pressure control to <130/80 mmHg did not reduce mortality after adjustment for risk factors. Patients with systolic blood pressure maintained at 110 mmHg had a 2.8-fold increase in mortality compared with patients whose systolic blood pressure was maintained at 130139 mmHg. For diastolic blood pressure there were significant increases in all-cause mortality of 32 percent with pressures of 7074 mmHg, and 89 percent with pressures of <70 mmHg, compared with pressures of 8084 mmHg. The findings were similar for patients without known cardiovascular disease. Among patients with newly diagnosed type 2 diabetes, too strict a control of blood pressure may be hazardous.
Vamos EP et al. Association of systolic and diastolic blood pressure and all cause mortality in people with newly diagnosed type 2 diabetes: retrospective cohort study. BMJ 2012; 345 (Sept 22): 18 (e5567).

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January 2013

In Practice

Managing COPD in primary care

Professor Neil Barnes
London Chest Hospital, London, UK

Dr. Ong Kian Chung

President, Singapore COPD Association Mt Elizabeth Medical Centre, Singapore

Introduction Chronic obstructive pulmonary disease (COPD) is a chronic disease involving airways inflammation that affects about 5 percent of the older population. While cigarette smoking is the biggest risk factor, long-term exposure to indoor air pollution caused by burning of biomass fuels, occupational dust and chemicals and underdeveloped lungs are among other contributing factors. Until recently, it was thought that only 15 to 20 percent of cigarette smokers would eventually develop COPD at some stage in their lives. It is now known that about half of smokers will develop this debilitating disease. By 2020, COPD will be the third leading cause of death worldwide (after ischemic heart disease and stroke) and the sixth leading cause of disability. In many countries, COPD exacerbations are now either the most common or second most common reason for hospitalization with an identifiable medical condition. The situation is likely to get worse due to an aging population. That puts general practice in an even more important position to diagnose the patients before their lung function deteriorates irreversibly. COPD is characterized by increased CD8+ T cells and macrophages in biopsies, and in-

creased neutrophils in sputum. Diagnosis Diagnosis of COPD is a two-step process. The first is making a clinical diagnosis. A GP should suspect COPD if a smoker or exsmoker complains of dyspnea, cough, frequent chest infections and chronic sputum production. But first, rule out other diseases including asthma, tuberculosis, congestive heart failure, obliterative bronchiolitis and diffuse panbronchiolitis using differential diagnosis. The second part of the diagnosis is equally as important but happens rather patchily. It consists of the need to confirm clinical diagnosis by performing spirometry lung function test (LFT). It is a fairly simple procedure and doesnt cost much. Still, many GPs dont use it. Thats akin to managing someone with hypertension without measuring their blood pressure. In spirometry, more than 80 percent of the values of forced expiratory volume in one second (FEV1), as predicted on the basis of an individual patients age, sex and ethnicity, will classify them as having a mild COPD, whereas 30 to 50 percent of predicted FAV1 indicates severe disease. A FEV1 of less than 30 percent of the predicted value suggests a very severe COPD.

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January 2013

In Practice

While confirming the COPD diagnosis, the level of lung function also tells you something about their likelihood of problems in the future. The worse their lung function, the more likely they are to run into other health problems in the future. Practice guidelines The revised Global initiative for chronic Obstructive Lung Disease (GOLD) guidelines define two separate aims in COPD management: symptom reduction and risk reduction. The COPD Assessment Test (CAT) is an 8-point unidimensional measure of health status impairment. The score ranges from 0 to 40. A score of more than 10 indicates a more symptomatic patient who should be placed into B or D groups of the assessment chart. The 0-4 point modified British Medical Research Council (mMRC) dyspnea scale also helps understand the level of breathlessness (see Figure). The assessment of risk can either be done using the FEV1/FVC (forced vital capacity) ratio with spirometry, using 1-4 GOLD classification of airflow limitation or it can be based on the number of exacerbations the patient has had during the past year. Post bronchodilator FEV1/FVC of <0.70 confirms Figure: Assessment of COPD
Risk (Gold Classification of Airflow Limitation)
4

The two main aims of COPD management should be to reduce a patients symptoms and their risk of disease progression.

persistent airflow limitation. Patients with a history of 2 or more exacerbations per year or very severe airflow limitation belong to the high risk groups C or D. Treatment Treatment strategy for COPD is similar to ischemic heart disease as it uses a range of different drug and non-drug therapies such as smoking cessation, lifestyle changes, flu vaccination to help prevent chest infections, pulmonary rehabilitation, and drug therapy. The latter includes short and long acting 2agonists (SABA/LABA) and muscarinic antagonists (SAMA/LAMA), inhaled corticosteroids (ICS), phosphodiesterase-4 (PDE-4) inhibitors and long-acting anticholinergics such as tiotropium that are commonly recommended in varying combinations, depending on the disease severity. Patients with COPD are at high risk of developing other comorbidities such as cardiovascular disease, osteoporosis, depression and anxiety, skeletal muscle dysfunction, metabolic syndrome and lung cancer that can have a significant impact on their prognosis. Depending on their clinical condition, the GOLD guidelines recommend that an appropriate fluid bal-

(C)
3 2

(D)

2 or more Risk (Exacerbation history)

(A)
mMRC 0-1 CAT <10

(B)
mMRC 2 CAT 10

Less than 2

Symptoms (mMRC or CAT score)

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January 2013

In Practice
Compliance Compliance with drug or non-drug therapies can be a challenge. A good doctorpatient relationship can, however, help improve compliance. If patients feel that the doctor has listened to them and that the treatment addresses their needs, they are more likely to stick to the drug and nondrug treatment regimen. A simple drug regimen also helps. If patients are required to take multiple medications at different times of the day, they have more chances to slip up. One of the problems with COPD patients is that they begin to exercise less because they easily get short of breath. And because they exercise less, they end up developing other health problems. Thats why it is important to recommend physical activity at an early stage of COPD. The more they keep themselves active, the better it will be not just for their COPD symptoms, but also for other associated chronic diseases.

ance with special attention to administration of diuretics, anticoagulants, and treatment of comorbidities and nutritional deficiencies should be considered. COPD exacerbations deteriorate quality of life, reduce lung function that becomes irreversible in many patients, lead to avoidable hospitalizations and death. Although frequent exacerbations amount to two or more breathing attacks in a year, each patient needs to be judged individually. If someone ends up in a hospital just once with a really bad exacerbation, that should be taken as a red flag from the risk reduction point of view. Emphasis on risk reduction is, in fact, the most important change over the previous GOLD guidelines. Just as in the management of ischemic heart disease you want to stop your patients having angina and chest pain, but also want to stop them from having a myocardial infarct. That concept is familiar to most general practitioners because it is how they approach the treatment of other chronic diseases. The aims of COPD management

Reduce symptoms: Relieve symptoms, improve exercise tolerance, improve health status Reduce risk: Prevent disease progression, prevent and treat exacerbations, reduce mortality

Online Resources:
GOLD guidelines www.goldcopd.org Improving the Differential Diagnosis of Chronic Obstructive Pulmonary Disease in Primary Care www.goo.gl/ZraLr American Lung Association www.lung.org/lung-disease/copd/

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January 2013

Calendar
International Meeting on Emerging Diseases and Surveillance (IMED 2013)
15/2/2013 to 18/2/2013 Location: Vienna, Austria Info: International Society for Infectious Diseases Tel: (617) 277 0551 Fax: (617) 278 9113 Email: info@isid.org Website: www.isid.org/imed/Index.shtml

January
16th Bangkok International Symposium on HIV Medicine
16/1/2013 to 18/1/2013 Location: Bangkok, Thailand Info: Ms. Jeerakan Janhom (Secretariat) Tel: (66) 2 652 3040 Ext. 102 Fax: (66) 2 254 7574 E-mail: jeerakan.j@hivnat.org Website: www.hivnat.org/bangkoksymposium

28th Congress of the Asia-Pacific Academy of Ophthalmology

17/1/2013 to 20/1/2013 Location: Hyderabad, India Info: APAO Secretariat Tel: (852) 3943 5827 Fax: (852) 2715 9490 Email: secretariat@apaophth.org Website: www.apaoindia2013.org

Asian Pacific Society of Cardiology 2013 Congress

21/2/2013 to 24/2/2013 Location: Pattaya, Thailand Info: Kenes Asia (Thailand Office) Tel: (66) 2 748-7881 Fax: (66) 2 748-7880 Email: apscoffice2013@apsc2013.org Website: www2.kenes.com/apsc2013/pages/home.aspx

Emergency Medicine 2013

23/1/2013 to 24/1/2013 Location: London, UK Info: MA Healthcare Conferences (London) Tel: (44) 20 7501 6762 Fax: (44) 20 7978 8319 Email: conferences@markallengroup.com Website: www.mahealthcareevents.co.uk/

March
23rd Conference of the Asia Pacific Association for the Study of the Liver
7/3/2013 to 10/3/2013 Location: Singapore Info: Gastroenterological Society of Singapore, The Asian Pacific Association for the Study of the Liver Tel: (65) 6292 4710 Fax: (65) 6292 4721 Email: apaslconference@kenes.com Website: www.apaslconference.org

4th International Conference on Legal Medicine, Medical Negligence and Litigation in Medical Practice(IAMLE-2013)
25/1/2013 to 27/1/2013 Location: Thiruvananthapuram, Kerala, India Info: Prof. R.K.Sharma, Chairman - IAMLE 2013 Tel: (91)11 4158 6401/402 Email: rksharma1@gmail.com, info@dreamztravel.net Website: www.iamleconf.in

62nd American College of Cardiology (ACC) Annual Scientific Session

9/3/2013 to 11/3/2013 Location: San Francisco, California, US Info: American College of Cardiology Foundation Tel: (415) 800 699 5113 Email: accregistration@jspargo.com Website: www.accscientificsession.org/Pages/home.aspx

February
Food Allergy and Anaphylaxis Meeting (FAAM) 2013
7/2/2013 to 9/2/2013 Location: Nice, France Info: EAACI FAAM 2013 Secretariat Tel: (33) 1 7039 3554 Fax: (33) 1 5385 8283 Email: infoFAAM2013@mci-group.com Website: www.eaaci-faam.org/

28th Annual European Association of Urology Congress

15/3/2013 to 19/3/2013 Location: Milan, Italy Info: European Association of Urology Tel: (39) 2 4342 6275 Fax: (39) 2 4801 0270 Email: info@eaumilan2013.org Website: www.eaumilan2013.org

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January 2013

Calendar

4th Biennial Congress of the Asian-Pacific Hepato-Pancreato-Biliary Association

27/3/2013 to 30/3/2013 Location: Shanghai, China Info: Asian Pacific Hepato-Pancreato-Biliary Association Tel: (86) 21 350 30066 Fax: (86) 21 655 62400 Email: secretariat@aphpba2013shanghai.org Website: www.aphpba2013shanghai.org

April
European Congress on Osteoporosis and Osteoarthritis
17/4/2013 to 20/4/2013 Location: Rome, Italy Info: International Osteoporosis Foundation Tel: (32) 4 254 1225 Email: info@iofbonehealth.org Website: www.ecceo13-iof.org

48th European Association for the Study of the Liver

24/4/2013 to 28/4/2013 Location: Amsterdam, Netherlands Info: European Association for the Study of the Liver Tel: (31) 20 549 1212 Fax: (31) 20 646 4469 Email: devi.sonida-mey@easloffice.eu Website: www.easl.eu/_the-International-liver-congress/ general-information

5th Association of Southeast Asian Pain Societies Conference

28/4/2013 to 5/5/2013 Location: Singapore Info: Pain Association of Singapore Tel: (65) 6292 4710 Fax: (65) 6292 4721 Email: aseaps2013@kenes.com Website: www.aseaps2013.org Tel: (86) 21 350 30066 Fax: (86) 21 655 62400 Email: secretariat@aphpba2013shanghai.org Website: www.aphpba2013shanghai.org

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January 2013

After Hours

Alan Sim

SERVE UP HEALTHY GOURMET ON A TRAY

William Tay

Radha Chitale

he kitchens at Mount Elizabeth Novena Hospital fire up at 5 each morning. Chefs at seven different stations begin chopping vegetables, cooking rice, reviewing menus and making preparations for breakfast. Executive Chef Alan Sim stops by each section every day to check a recipe or tweak a garnish. Each meal is calibrated to precise amounts of calories, fats, vitamins and minerals and carefully vetted by dieticians. With such a clinical approach, it is no wonder that hospital food is not usually associated with gastronomic heights; more along the lines of bland, wilting fare, to be endured like another hospital procedure. But if patients dont eat because they have no appetite, because they dont like the food being served they are missing the nutrition that is a critical part of care and recovery. Patients who eat the least tend to have the worst clinical outcomes and are at increased risk of malnutrition. [Nutr Clin Pract 2012;27:274-80] Behind the scenes of many of Singapores hospitals, teams of chefs, nutritionists and dieticians work to put together healthy menus that dont compromise on flavor. We need to provide food that will change

the entire perception of hospital food, Sim said. Know thy dish Sims background is largely in hotel kitchens, like many chefs who have found their way to the health care industry. They are no strangers to producing meals on a large scale. A large public hospital like Singapore General Hospital (SGH) serves about 4,000 meals per day. But cooking within rigid nutritional guidelines can pose a challenge for chefs used to prioritizing flavor. To help kitchen staff understand how to put together a balanced meal, hospital dieticians brief them on nutrition, dietary guidelines, therapeutic diets for diabetic or cancer patients, for example, and how to use substitute ingredients based on patient needs. For normal meals, hospitals follow the dietary guidelines recommended by the Ministry of Health. However, a diabetic patient will need meals that contain less sugar and more vegetables. A hypertensive patient will need meals low in salt. Meals may also need to be altered for vegetarian or Halal requirements. I have to be precise. I need to know what makes it into the ingredients and composition of a dish and also the nutrients that go into that, said Ms. Poh Leng, one of the dieticians

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After Hours
who worked with Sim to develop the menu at Mount Elizabeth Novena. That way, in case I need to modify the diet from the normal menu, I can. In a food that has a milk product, I might suggest a soy bean. Diabetic diets are the most common therapeutic diets offered in hospitals but kitchens can also offer meals that are low in fiber for colorectal surgery patients or low in iodine (no seafood or processed food) for patients on radioactive cancer treatment. Research and development Once the dietician has balanced the calories, fats, sugars, proteins and other components of patient meals, the chefs can get busy in the kitchen and this is where they need to be creative because their old flavor tools are no longer at their disposal. We seldom see butter, Sim sighed. Also gone are sugars, coconut milk, fried foods, white rice, and liberal sprinkles of salt. In their place: brown rice, yogurt, tofu and egg whites. Some substitutions are easy canola or olive oils instead of palm oil, for example, which is high in saturated fat. Others modifications require more innovation. Khoo Teck Puat Hospital Executive Chef William Tay said he reduces stocks to concentrate the natural flavor and cut down on added salt. Tamarind and yogurt can be subbed into curries for seasoning instead of salt and coconut milk to reduce sodium and fat. I like to use some local herbs like lemongrass and pandan leaf for flavor, especially when cooking western style, he added. Cooking techniques can lighten a dish. Roasting, steaming, stir frying in less oil and sous vide are preferable to frying. Another trick for sticking to a calorie count without compromising taste is to manage portions. If you want to cook food that is suitable for every patient, change the portion size, Tay said. Good food is not always healthy but it depends on how you portion it. Looking good enough to eat Still, chicken rice served in a hospital wont taste like the same dish from a hawker stall. That is why presentation counts for a lot when serving hospital meals. Both Tay and Sim said they always try to impress patients visually.

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After Hours
Hospitals get feedback on meals through patient rounds by kitchen staff and random surveys and incorporate their findings into future meal planning. Chefs and dieticians volley recipes back and forth to make sure each meal is nutritionally complete and tasty. Unlike food in restaurants, meals in a hospital must contribute to healing and recovery. Patients depend on us to supply the nutrients in the right balance to augment the physicians treatment, Koay said. The food supplied also serves as examples for them to comply with upon discharge. That is why we show and tell patients, especially those on therapeutic restrictions, how modifications can be made.

My main concern is to cook health, eat healthy... but we want to make people say wow! Tay said. Instead of mixing all the food together, Id rather do a garnish and a nice presentation. Ms Koay Saw Lan, senior manager of Food Services at SGH, said they use nicely designed crockery, tray liners, and clear food covers to make meals look good. These visual cues can help revive ill patients appetites and keep them on the path to recovery. What you want to look forward to is a new tray with a nice meal for you. Something thats appetizing and makes you want to eat, said Ms. Beatrice Pung, chief dietician at Mount Elizabeth Hospital.

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January 2013

Humor

I want you to stop eating immediately!

It was supposed to be a closed casket, but apparently he swallowed a Viagra pill before he died!

Hey, wait a minute! Your private health insurance doesnt cover diseases!

Quick! To the maternity ward at the St. Vincent Hospital! And relax, Im just visiting someone!

How did the facelift go?

Unfortunately, your insurance does not cover this kind of injury!

The voices in your head are not the result of schizophrenia. You forgot to turn off your iPod!

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